Out With the Bad: Efflux in Klebsiella pneumoniae

Phagehunter.org is proud to announce an article by guest author, E. Ohneck, of Emory University, as she discusses the importance of efflux pumps in bacterial systems.

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The Resistance-Nodulation-Division (RND) family of efflux pumps is widely utilized, especially among Gram-negative bacteria, for the export of a diverse array of antimicrobial agents from the bacterial interior, making these efflux systems important in multidrug resistance (1). RND family pumps are composed of three parts: a transporter protein in the inner cytoplasmic membrane, an outer membrane protein channel, and an accessory protein that connects the two (1). The AcrAB-TolC efflux pump is one such efflux system found in multiple Gram-negative bacteria, including Escherichia coli and Salmonella enterica serovar Typhimurium (1).

In their recent study, presented in a paper entitled “Klebsiella pneumoniae AcrAB efflux pump contributes to antimicrobial resistance and virulence,” Padilla et al confirm a role in multidrug resistance for the AcrAB-TolC efflux pump of K. pneumoniae, a highly prevalent nosocomial enterobacterial pathogen responsible for both urinary tract infections and bacterial pneumonia.

Through the use of knockout strains deficient in AcrB, the transporter protein component of the pump, the authors show the importance of AcrAB-TolC in resistance to β-lactams, aminoglycosides, quinolones, and other antibiotics (2). Interestingly, these AcrB knockouts were also significantly more susceptible to human antimicrobial peptides and were less able to colonize mice lungs and cause pneumonia, effects which were shown to be attributable to AcrAB-TolC deficiency (2).

These results have several important implications. First, like other RND family efflux pumps, the AcrAB-TolC efflux pump likely contributes significantly to the multidrug resistant phenotype observed in some K. pneumoniae strains, due to its broad antimicrobial substrate specificity (2). Secondly, AcrAB-TolC may also mediate resistance to host antimicrobial peptides (2). To date, this phenomenon has been established for relatively few efflux pumps, one of the best characterized examples being MtrCDE-mediated resistance to the host antimicrobial peptide LL-37 in Neisseria gonorrhoeae (3). The ability of bacterial efflux systems to pump out host-derived antimicrobial agents provides pathogens with an important mechanism of protection against one of the first-line defenses of the innate immune system.

Taken together, these conclusions raise the concern that antibiotic treatment can select not only for increasingly antibiotic resistant strains, but also for strains better able to resist the host immune defenses, and thus better able to cause disease. Clearly, efflux-mediated resistance to host antimicrobial compounds and its relation to antibiotic resistance and pathogenesis is an area that demands further study in order to develop efficient methods of combating the increasing number of multidrug resistant bacteria.

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Sources:
1. Piddock LJV. Multidrug-resistance efflux pumps—not just for resistance. Nat Rev Microbiol. 2006 Aug 4(8): 629 – 36.

2. Padilla E, Llobet E, Doménech-Sánchez A, Martínez-Martínez L, Bengoechea JA, & Albertí S (2009). Klebsiella pneumoniae AcrAB efflux pump contributes to antimicrobial resistance and virulence. Antimicrobial agents and chemotherapy PMID: 19858254

3. 3. Shafer WM, Qu X, Waring AJ, Lehrer RI. Modulation of Neisseria gonorrhoeae susceptibility to vertebrate antibacterial peptides due to a member of the resistance/nodulation/division efflux pump family. Proc Natl Acad Sci U S A. 1998 Feb 17;95(4):1829-33.

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Other Articles of Interest:
The Origins of Antibiotic Resistance
Wild Bacteria that eat Our Antibiotics? Of Course!
Antibiotic Treatment: Increasing the Rate of Genetic Exchange